Inclusion complexes of 3-morpholino-sydnonimine or its salts or

Details Inclusion complexes of 3-morpholino-sydnonimine or its salts or Inclusion complexes of 3-morpholino-sydnonimine or its salts or

1992-01-02

1994-03-29

Griffin, Ronald W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536103, 424464, 424499, 514821, 514969, C07D27104, C07D29530, A61K 3141, C08B 3716

Patent

active

052984966

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Phase of PCT/HU91/00013 filed Mar. 28, 1991 and based upon Hungarian national application 1869/90 of Mar. 28, 1990 (amended Jun. 27, 1990) under the International Convention.
1. Field of the Invention
The invention relates to the inclusion complexes of 3-morpholino-sydnonimine (SIN-1) or its salts or its open ring "A" form tautomer (SIN-1A: N-nitroso-N-morpholino-amino-acetonitrile) formed with cyclodextrin derivatives, to the process of preparation and to pharmaceutical compositions containing them as active ingredients. The open ring "A" form plays an important role, its formation is predominant for NO (nitric oxide) radical liberation.
2. Background of the Invention
Molsidomin (N-ethoxycarbonyl-3-morpholino-sydnonimine, SIN-10) is a well-known antianginal agent. In therapy it is widely used for the treatment and prevention of angina in the case of heart insufficiency, in the state of heart infarct. The therapeutic effect of Molsidomin can be attributed mainly to its first active metabolite to the 3-morpholino-sydnonimine, which originates mainly in the liver by enzymatic hydrolysis and by subsequent effect of the decarboxylase enzyme. Thus the SIN-1 possesses a therapeutic advantage too compared to Molsidomin, that is its efficacy is quicker and more definite. Its disadvantage is that it can be used only in the form of intravenous injections.
The sydnonimine derivatives are extremely light-sensitive. Upon to irradiation with artificial or natural light for only a short time they will be decomposed quickly. In the course of photolysis pharmacologically inactive, but harmless decomposition products as e.g. morpholine, ammonia, ethyl alcohol, carbondioxyde form. The aim of some patents is the photostabilization of sydnonimine derivatives by the addition of different additives. (European Patent Specification No. 206219 and GFR Patent Specification No. 3.346.638).
The light-sensitivity can fairly be avoided in dry state and in solution by suitable storage (in a well-closed dark flask wrapped with black paper).
It can be generally said that the sydnonimine derivatives are sensitive to extreme pH values, and are decomposed quickly. The final product of the chemical and metabolitic decomposition of Molsidomin is the SIN 1C (cyanomethylene-amino-morpholine), an inactive metabolite. In the use of SIN 1 as a medicament the problems of chemical stability are coming to the fore. The substance decomposes quickly in a neutral-aqueous solution, it is sensitive to the pH value and it is stable only in a strong acidic medium (pH 1-2). Above pH 2 it decomposes quickly, to the inactive metabolite SIN 1C, that is connected with the loss of therapeutic activity. The SIN 1.fwdarw.SIN 1C transformation is the result of base catalyzed hydrolytic decomposition. The process is strictly pH dependent, e.g. to achieve a decomposition of 10% (SIN 1C) 53 sec. at a pH value of 8, 15 hours at a pH of 6, 67 days at a pH of 4, and 13 years at a pH of 1-2 are necessary. (Chem. Pharm. Bull. 19/6 1079, 1971). SIN 1 is also decomposed in a diluted aqueous solution stored in diffused lighting in 1-3 days. The decomposition can be followed from the UV spectrum directly. The value of the absorption maximum is shifted gradually from 291.+-.1 nm to 278.+-.1 while the value of absorption increases continuously, which is in harmony with the data of the literature: the .lambda. max. value of SIN 1 is 291.+-.1 nm, the specific absorption coefficient A.sup.1% =520, while the SIN 1C .lambda. max. is 278.+-.1 nm, its molar absorption coefficient .epsilon.=17000 A.sup.1% =1220.
SIN 1 applied orally is not effective; between pH 1-2 SIN 1 has presumably a strongly ionized state of favourable chemical stability, which on the other hand is not favorable to the resorption from the G1 tract. Moving along from the stomach at a more basic pH in the sense of the above mentioned facts SIN 1 is transformed quickly into the inactive SIN 1C metabolite. The low dose of the SIN 1 applied is favorabl

REFERENCES:
patent: 4786507 (1988-11-01), Schmidt
patent: 4834985 (1989-05-01), Elger et al.
patent: 4869904 (1989-09-01), Uekama et al.
patent: 5120546 (1992-06-01), Hansen et al.

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